Extended Data Table 5. Characterization of variant associations through conditional analysis.

For each locus, significantly associated SNVs are presented. Unconditional p-values are given in italics, and conditional p-values are shown for each pair of SNVs (p-values are for SNVs in the “Variant” column, with SNVs listed in header included as covariates in association analysis). The IRS1 and PPARG non-coding associations were characterized using exact conditional analysis in 38,738 samples from the GoT2D genome-wide imputed meta-analysis. Conditional analysis for coding variant associations was, for most loci, restricted to the exome array genotypes (28,305 cases, 51,549 controls). At THADA and RREB1, neither the non-coding lead GWAS SNVs nor close proxies were typed on the exome array, so approximate conditional analyses were undertaken using GCTA in 44,414 samples from the GoT2D genome-wide imputed meta-analysis (Methods). For several of these loci, unconditional association p-values for these loci do not reach genome-wide significance as sample sizes are smaller. At the GPSM1 locus, the previously reported GWAS SNV was not available on exome array and too poorly imputed in the GoT2D meta-analysis to allow meaningful inference

Locus	Variant	MAF	Unconditional and conditional association p-values				Interpretation
Non-coding variant associations characterized in 38,738 samples in GoT2D genome wide imputed meta analysis
IRS1			rs78124264	rs7578326	rs2943640	rs2943641	The association signal rs78124264 and the GWAS SNPs at this locus are distinct. Signals are not extinguished in reciprocal conditional analysis. Previous GWAS signals are not mediated through rs78124264, which represents a distinct association signal at this locus.
	rs78124264	0.022	8.5×10−5	2.5×10−7*	2.5×10−7*	2.5×10−7*
	rs7578326¶	0.35	1.2×10−7	1.1×10−5	n.d.	n.d.
	rs2943640¶	0.35	2.5×10−11	n.d.	4.5×10−10	n.d.
	rs2943641¶	0.36	9.0×10−12	n.d.	n.d.	1.5×10−10
PPARG			rs79856023	rs1801282			The association signal rs79856023 and the GWAS SNP at this locus are distinct. Signals are not extinguished in reciprocal conditional analysis. Previous GWAS signal is not mediated through rs79856023, which represents a distinct association signal at this locus.
	rs79856023	0.022	1.2×10−4	9.2×10−7
	rs1801282¶	0.13	1.6×10−6	1.2×10−5
Coding variant associations characterized in 28,305 cases and 51,549 controls typed on exome array
PAM			Asp563Gly (PAM)	Ser1207Gly (PPIP5K2)			Association signals for PAM Asp563Gly and PPIP5K2 Ser1207Gly are indistinguishable in reciprocal conditional analysis. Gene biology, as well as previous reports of additional PAM variants associated with T2D in Icelandic cohorts, highlights PAM as the probable transcript at this locus.
	Asp563Gly	0.054	1.7×10−7	0.24
	Ser1207Gly	0.054	0.30	1.0×10−6
MTMR3-ASCC2			Asn960Ser (MTMR3)	Val123Ile (ASCC2)	Asp407His (ASCC2)	Pro423Ser (ASCC2)	Association signals for the MTMR3 and ASCC2 coding variants are indistinguishable in reciprocal conditional analysis. The MTMR3 Asn960Ser variant has the strongest signal, and highlights MTMR3 as the most likely effector transcript at this locus.
	Asn960Ser	0.083	3.2×10−6	0.022	0.027	0.022
	Val123Ile	0.083	0.15	2.0×10−5	0.066	0.76
	Asp407His	0.083	0.18	0.99	1.9×10−5	0.88
	Pro423Ser	0.083	0.18	0.67	0.98	2.0×10−5
KCNJ11-ABCC8			Val337Ile (KCNJ11)	Lys23Glu (KCNJ11)	Ala1369Ser (ABCC8)		Association signals for KCNJ11 Val337Ile and Lys23Glu and ABCC8 Ala1369Ser are indistinguishable in reciprocal conditional analysis. The relative causal contributions of the two genes, making up the two components of the sulfonlylurea-responsive potassium channel, are indistinguishable on statistical grounds.
	Val337Ile	0.40	3.4×10−9	0.17	0.049
	Lys23Glu	0.40	0.48	5.1×10−9	0.082
	Ala1369Ser	0.40	0.68	0.84	2.3×10−8
WFS1			Val333Ile	Asn500Asn	Arg611His	rs4689388	Association signals for the WFS1 coding variants are indistinguishable from each other and the previously reported non-coding GWAS SNP at this locus in reciprocal conditional analysis. WFS1 is the likely effector transcript for the non-coding GWAS signal at this locus, although the causal variant in the gene is unclear.
	Val333Ile	0.30	9.3×10−12	0.024	0.00070	0.0030
	Asn500Asn	0.41	0.0070	2.0×10−12	0.0049	0.027
	Arg611His	0.47	0.020	0.62	1.3×10−10	0.19
	rs4689388¶	0.43	0.011	0.62	0.024	2.3×10−11
CILP2-TM6SF2			Glu167Lys (TM6SF2)	rs10401969			Association signals for TM6SF2 Glu167Lys and the previously reported non-coding GWAS SNP at this locus are indistinguishable from each other in reciprocal conditional analysis. TM6SF2 is the probable effector transcript for the non-coding GWAS signal at this locus, with the effect mediated through Glu167Lys.
	Glu167Lys	0.082	1.9×10−7	0.52
	rs10401969¶	0.083	0.62	4.2×10−7
GRB14-COBLL1			Asn939Asp (COBLL1)	rs13389219			Association signals for COBLL1 Asn939Asp and the previously reported non-coding GWAS SNP at this locus are partially correlated. The association signal for the GWAS signal is not entirely extinguished in reciprocal conditional analysis. COBLL1 is a candidate effector transcript for the GWAS signal at this locus.
	Asn939Asp	0.12	4.7×10−11	3.00×10−5
	rs13389219¶	0.39	7.0×10−5	1.9×10−10
Coding variant associations characterized in 44,414 samples in GoT2D genome wide imputed meta analysis
THADA			Cys1605Tyr	rs10203174			Association signals THADA Cys1605Tyr and the GWAS SNP are partially correlated. The association signal for the GWAS SNP is not entirely extinguished in reciprocal conditional analysis. THADA is a candidate effector transcript for the GWAS signal at this locus.
	Cys1605Tyr	0.10	0.00035	0.92
	rs10203174¶	0.10	0.0063	5.7×10−6
RREB1			Asp1171Asn	rs9502570			The association signals of RREB1 Asp1171Asn and the GWAS SNP at this locus are distinct. The association signal is not extinguished in reciprocal conditional analysis. Previous GWAS signal is not mediated through RREB1 Asp1171Asn. RREB1 Asp1171Asn represents a distinct association signal at this locus.
	Asp1171Asn	0.11	0.0018	0.0017
	rs9502570¶	0.28	0.0037	0.0042

^*Conditional analysis was performed once for rs78124264 with all three previously known GWAS variants included as covariates.

^¶Non-coding GWAS lead variant.

n.d. indicates “not determined.”